Despite tremendous scientific efforts aimed at understanding the molecular biology of pancreatic cancer, conventional treatment approaches have had little impact on the course of the disease. Thus, studies identifying key determinants in pancreatic cancer and pancreatic cancer stem cell (CSCs) can provide both biomarkers of PDAC aggressiveness and potentially optimal targets to overcome chemoresistance. We have found that NFATc1 and NFATc2 (NFATc1/c2) are ectopically expressed in PDAC samples, respectively and that pharmacologic inhibition or RNAi toward NFATc1/c2 reduces PDAC cell growth in vitro and in vivo. Interestingly, we show that expression of a constitutive nuclear NFATc1 in the developing mouse pancreas using p48-cre along with KRasG12D develop invasive PDAC by 16-20 weeks of age, thus demonstrating that NFATc1 is a potent oncogene in this disease. We performed NFATc1 ChIP-seq in order to gain insight into the transcriptional network driven by this oncogenic/inflammatory transcription factor. We identified nearly 1800 NFATc1-target genes, two-thirds of which are dependent on an interaction with STAT3. Significantly, most of the NFAT/STAT3-regulated gene networks are involved in inflammation, proliferation and metastasis. Moreover, we demonstrate for the first time that NFATc1 is enriched in pancreatic CSCs generated from PDAC cell lines and CSC self-renewal is inhibited by pharmacologically targeting NFAT nuclear activity through the use of cyclosporine A (CsA). However, the mechanisms by which NFATs regulate CSC self-renewal and or chemoresistance are unclear. Furthermore, we show that PDAC cell lines, which express NFATc1/c2 are sensitive to CsA and synergize with gemcitabine to kill tumor cells in vitro and limit tumor growth in vivo. Despite these preliminary observations, information regarding NFATc1/c2 target genes in human PDAC is lacking and mechanisms by which NFATc1/c2 regulate pancreatic cancer cell growth remain to be determined. Furthermore it is unknown whether ectopic expression of NFATc1/c2 correlates with specific clinical features of the disease, participates in pancreatic CSC biology, or represents a therapeutic target in the clinic. These outstanding questions will be addressed in this application.